Colonization of the nasopharynx is a prerequisite to disease with the pathogen Streptococcus pneumoniae. With >90 different capsular serotypes, the initial success of the 7-valent conjugate pneumococcal vaccine (PCV7) has been overshadowed by reports of serotype replacement resulting in colonization and disease with previously rare strains. This suggests that intraspecies competition among pneumococci occurs in the nasopharynx, and the loss of competitive strains through PCV7 induced herd immunity has resulted in the emergence of previously out competed strains. This project uses two aims to address the contribution of antimicrobial peptides made by S. pneumoniae called pneumocins to intraspecies competition. The first aim addresses the mechanism of regulation of pneumocin expression which involves modifications at the transcriptional and post transcriptional level. The regulatory circuit will be studied with a particular emphasis on the state of expression during colonization. The second aim will focus on factors influencing the spectrum of activity of the various pneumocin MN isotypes as well as describing the ability of these peptides to clear colonization by suseptible strains in a mouse model of simultaneous colonization by mutliple strains. This application describes a 4-year program designed to provide Dr. Suzanne Dawid with the skills required to become an independent scientist in the field of microbial pathogenesis. Dr. Dawid has completed a fellowship in pediatric infectious diseases and will be mentored by Dr. Jeffrey Weiser, a leader in the field of bacterial pathogenesis with a particular focus on S. pneumoniae colonization. The project involves didactic study in the fields of genetics and microbial pathogenesis as well as in-depth laboratory experience in molecular biology, biochemistry and in vivo modeling. Relevance: Preexisting intraspecies competition between isolates of S. pneumoniae mediated by the production of antimicrobial peptides called pneumocins may explain the emergence of previously rare strains following widespread vaccination of the population. This detailed study of the forces driving this competition will aid in our understanding of microbial ecology and complex interactions involved in successful colonization, the initial step in all disease by this major pathogen. [unreadable] [unreadable] [unreadable] [unreadable]